JPH10324631A - Immunoglobulin e antibody formation inhibitor - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject inhibitor that has an inhibitory action to inhibit the formation of IgE antibody produced against extraneous antigens by using a specific compound as an active ingredient. SOLUTION: This inhibitor contains, as an active ingredient, a compound represented by formula I [R<1> is H, a lower alkyl, a lower alkoxy; R<2> is hydroxy, a halogen; R<3> is H, an organic group; Z is O, formula II (n is 0, 1, 2)] or its pharmaceutically acceptable salt. This compound can be orally or parenterally administered in a dose of 3.2-32 mg/kg and gives a composition that is effective for treatment and prevention of the inflammation and pains in joints and muscles, collagen diseases and a variety of immunological disease in human and animals.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to an IgE antibody production inhibitor containing a compound represented by the following general formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient.

[0002]

BACKGROUND OF THE INVENTION The compound represented by the following general formula (I) of the present invention is a known substance as described in WO93 / 15083, for example, an autoantibody produced against an autoantigen. It is known to have an immunomodulating action such as an action of suppressing the production of one kind of anti-DNA antibody, an anti-inflammatory action and an anti-cancer action. However, it has not been known that these compounds suppress the production of IgE antibodies produced against a foreign antigen.

[0003]

[0007] Compounds which have the effect of suppressing the production of IgE antibodies and are useful as pharmaceuticals are known, but there is still room for improvement in efficacy or toxicity. Are intended for the development of more useful medicines.

[0004]

The present invention relates to a compound of the formula (I)

Embedded image Wherein R ¹ is hydrogen, lower alkyl, lower alkoxy,
Lower alkylthio, halogen, nitro, amino or protected amino, R ² is hydroxy, protected hydroxy, halogen, amino or protected amino,
R ³ is hydrogen or an organic group, R ⁴ is hydrogen or lower alkyl, R ⁸ is hydrogen or lower alkyl, -Z- is-
O- or the formula:

Embedded image (Wherein n represents 0, 1 or 2), respectively. Or a pharmaceutically acceptable salt thereof as an active ingredient.

[0005] Suitable pharmaceutically acceptable salts of compound (I) are the customary non-toxic salts, which include, for example, salts with inorganic bases, such as alkali metal salts (eg sodium, potassium and the like). ), Alkaline earth metal salts (eg, calcium salt, magnesium salt, etc.), ammonium salts; salts with organic bases, such as organic amine salts (eg, triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, Dicyclohexylamine salts, N, N′-dibenzylethylenediamine salts and the like); inorganic acid addition salts (eg, hydrochloride,
Hydrobromide, sulfate, phosphate, etc.); organic carboxylic acid or sulfonic acid addition salts (eg, formate, acetate, trifluoroacetate, maleate, tartrate, methanesulfonate, benzenesulfonic acid) Salts, acid salts with a base, such as salts with basic or acidic amino acids (eg, arginine, aspartic acid, glutamic acid, etc.). In the description above and the following description of the present specification, preferred examples or specific examples of various definitions that the present invention does not include within the scope thereof are as follows.

The term "lower" is used to mean a group having 1 to 6, preferably 1 to 4, carbon atoms, unless otherwise specified. The term "higher" is used to mean a group having 7 to 20 carbon atoms unless otherwise specified. Preferred "lower alkyl" and suitable "lower alkyl moieties" in the expressions "lower alkylthio", "lower alkylsulfinyl" and "lower alkylsulfonyl" include methyl, ethyl, propyl, isopropyl, butyl, t-butyl, Examples thereof include linear or branched ones such as pentyl and hexyl, among which more preferred examples are C ₁ -C ₄ alkyl. Suitable "lower alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, t-butoxy, pentyloxy,
t-pentyloxy, hexyloxy and the like,
Among them, more preferred examples are C ₁ -C ₄ alkoxy. Suitable "halogens" include fluorine, chlorine, bromine and iodine. Suitable “protected hydroxy” includes acyloxy groups and the like. Suitable "protected amino" includes acylamino and the like.

"Acyloxy" and "acylamino"
Suitable "acyl moieties" in the expression include carbamoyl, aliphatic acyl groups, aromatic ring-containing acyl groups (hereinafter, referred to as aromatic acyl), and heterocyclic-containing acyl groups (hereinafter, heterocyclic acyl). . Preferred examples of the acyl are as follows: carbamoyl;
Lower or higher alkanoyls (e.g., formyl, acetyl, propanoyl, butanoyl, 2-methylpropanoyl, pentanoyl, 2,2-dimethylpropanoyl,
Hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, nonadecanoyl, icosanoyl, etc .; Ethoxycarbonyl, t-butoxycarbonyl, t
Lower or higher alkylsulfonyl (eg, methylsulfonyl, ethylsulfonyl, etc.); aliphatic acyl such as lower or higher alkoxysulfonyl (eg, methoxysulfonyl, ethoxysulfonyl, etc.); aroyl (eg, benzoyl) Alkanol (eg, phenyl (lower) alkanoyl (eg, phenylacetyl, phenylpropanoyl, phenylbutanoyl, phenylisobutanoyl, phenylpentanoyl, phenylhexanoyl, etc.), naphthyl (lower) ) Alkanoyl (eg, naphthylacetyl, naphthylpropanoyl,
Al (lower) alkenoyl [eg, phenyl (lower) alkenoyl (eg, phenylpropenoyl, phenylbutenoyl, phenylmethacryloyl, phenylpentenoyl, phenylhexenoyl, etc.), naphthyl (lower) alkenoyl (Eg, naphthylpropenoyl, naphthylbutenoyl, naphthylpentenoyl, etc.);

Aroxy (lower) alkoxycarbonyl [eg phenyl (lower) alkoxycarbonyl (eg benzyloxycarbonyl) etc.]; aryloxycarbonyl (eg phenoxycarbonyl, naphthyloxycarbonyl etc.); aryloxy (lower) alkanoyl (eg phenoxy) Acetyl, phenoxypropionyl and the like); arylglyoxyloyl (for example, phenylglyoxyloyl, naphthylglyoxyloyl and the like); aromatic acyl such as arenesulfonyl (for example, benzenesulfonyl, p-toluenesulfonyl and the like); heterocyclic carbonyl; heterocyclic ring (Lower) alkanoyls (eg thienylacetyl, thienylpropanoyl, thienylbutanoyl, thienylpentanoyl, thienylhexanoyl, Heterocyclic (lower) alkenoyl (eg, heterocyclic propenoyl, heterocyclic butenoyl, heterocyclic pentenoyl, heterocyclic hexenoyl, etc.); heterocyclic glyoxyloyl (eg, thiolylacetyl, thiadiazolylacetyl, tetrazolylacetyl, etc.); Heterocyclic acyl such as asiazolyl glyoxyloyl and thienyl glyoxyloyl); The above “heterocyclic carbonyl”, “heterocyclic (lower) alkanoyl”, “heterocyclic (lower) alkenoyl” and “heterocyclic glyoxyloyl”
Suitable heterocyclic moieties in the expression
It means a saturated or unsaturated monocyclic or polycyclic heterocyclic group containing at least one hetero atom such as an oxygen atom, a sulfur atom and a nitrogen atom.

Particularly preferred heterocyclic groups include 1 to 4
3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group containing two nitrogen atoms, such as pyrrolyl, pyrrolinyl, imidazolyl, pyrazolyl, pyridyl and its N
-Oxide, dihydropyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazolyl (e.g. 4H-1,
2,4-triazolyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, etc., tetrazolyl (eg, 1H-tetrazolyl, 2H-tetrazolyl, etc.); Containing a 3- to 8-membered (more preferably 5- or 6-membered) saturated heterocyclic monocyclic group, such as pyrrolidinyl, imidazolidinyl, piperidyl, piperazinyl and the like; an unsaturated condensed heterocyclic group containing 1-4 nitrogen atoms, for example, indolyl , Isoindolyl,
Indolinyl, indolizinyl, benzimidazolyl,
Quinolyl, tetrahydroquinolyl (for example, 1, 2,
3,4-tetrahydroquinolyl), isoquinolyl,
Tetrahydroisoquinolyl (for example, 1,2,3,4-
Tetrahydroisoquinolyl, etc.), indazolyl, quinoxalinyl, tetrahydroquinoxalinyl (eg, 1,2,3,4-tetrahydroquinoxalinyl),
Benzotriazolyl and the like; 1-2 oxygen atoms and 1-3
And 3 to 8 members containing nitrogen atoms (more preferably 5 to 8 members).
Or 6-membered) unsaturated heteromonocyclic group such as oxazolyl, isoxazolyl, oxadiazolyl (eg, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, etc.);
A 3-8 membered (more preferably 5 or 6 membered) saturated heteromonocyclic group containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as morpholinyl, sinodonyl and the like;

Unsaturated condensed heterocyclic groups containing 1-2 oxygen atoms and 1-3 nitrogen atoms, such as benzoxazolyl, benzooxadiazolyl, benzoxazinyl (for example, 2H-1, 4-benzoxazinyl, 4H
-1,4-benzoxazinyl, etc.), dihydrobenzoxazinyl (for example, 3,4-dihydro-2H-1,
4-benzooxazinyl and the like); a 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heteromonocyclic group containing 1-2 sulfur atoms and 1-3 nitrogen atoms, for example, Thiazolyl, isothiazolyl, thiadiazolyl (eg, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,5-thiadiazolyl, etc.), dihydrothiazinyl and the like; A 3-8 membered (more preferably 5 or 6 membered) saturated heteromonocyclic group containing a sulfur atom and 1 to 3 nitrogen atoms, such as thiazolidinyl; 3 to 8 containing 1 to 2 sulfur atoms Membered (more preferably 5 or 6 membered) unsaturated heteromonocyclic groups such as thienyl, dihydrodithiynyl, dihydrodithionyl, etc .; containing 1-2 sulfur atoms and 1-3 nitrogen atoms That unsaturated condensed heterocyclic group, for example benzothiazolyl, benzothiadiazolyl, benzothiazinyl (e.g. 2H-1,4 benzothiazinyl, 4H
-1,4-benzothiazinyl, etc.), dihydrobenzothiazinyl (for example, 3,4-dihydro-2H-1,4-
A 3-8 membered (more preferably 5 or 6 membered) unsaturated heteromonocyclic group containing one oxygen atom, such as furyl, etc .; one oxygen atom and one or two sulfur atoms A 3- to 8-membered (more preferably 5- or 6-membered) unsaturated heterocyclic monocyclic group such as dihydrooxathiinyl; an unsaturated fused heterocyclic group containing 1-2 sulfur atoms, such as benzo Thienyl, benzodithiynyl and the like; unsaturated fused heterocyclic groups containing one oxygen atom and one to two sulfur atoms, such as benzooxathiynyl and the like.

The above acyl is halogen, carboxy,
Protected carboxy, hydroxy, protected hydroxy, nitro, lower alkyl, heterocyclic group, cyclo (lower) alkyl, ar (lower) alkyl, lower alkoxy, aryl optionally having a substituent, etc. ,
It may have 1 to 10 identical or different substituents. Suitable "organic groups" include lower alkyl, lower alkenyl, lower alkynyl, aryl, ar (lower) alkyl, carboxy, acyl as exemplified above, and the like. Suitable "lower alkyl moieties" in the expression "ar (lower) alkyl" include those described above. Suitable "lower alkenyl" include vinyl, 1-propenyl, allyl, 1-methylallyl, 1 or 2 or 3-butenyl, 1 or 2 or 3 or 4-pentenyl, 1 or 2 or 3 or 4
Or 5-hexenyl and the like. Suitable "lower alkynyl" includes ethynyl, 1-propynyl, propargyl, 1-methylpropargyl, 1 or 2 or 3-butynyl, 1 or 2 or 3 or 4-pentynyl, 1 or 2 or 3 or 4 or 5- Hexynyl and the like.

Preferred "substituents" in the expression "carbamoyl optionally having one or two suitable substituents" include lower alkyl, heterocyclic groups, cyclo (lower) alkyl, and suitable substituents. Aryl and ar (lower) alkyl which may have a group; Suitable "aryl moieties" in the expressions "preferred" aryl "and" ar (lower) alkyl "include phenyl, naphthyl and the like. Suitable "substituents" in the expression "aryl optionally having substituent (s)" include lower alkylthio, halogen, lower alkylsulfinyl, acyl as exemplified above, and the like. Suitable "cyclo (lower) alkyl" includes cyclopropyl, cyclobutyl, cyclopentyl,
Examples thereof include a 3- to 8-membered cycloalkyl such as cyclohexyl, cycloheptyl, and cyclooctyl. Suitable "heterocyclic groups" include those described above.
Suitable "protected carboxy" includes esterified carboxy and the like. Preferred examples of the ester moiety include lower alkyl esters (eg, methyl ester, ethyl ester, propyl ester, isopropyl ester, butyl ester, isobutyl ester, t-butyl ester, pentyl ester, t-pentyl ester, hexyl ester, Lower alkenyl esters (eg, vinyl esters, allyl esters, etc.); lower alkynyl esters (eg, ethynyl esters, propynyl esters, etc.); lower alkoxyalkyl esters (eg, methoxymethyl esters, ethoxymethyl esters, isopropoxy). Methyl ester, 1-methoxyethyl ester, 1-ethoxyethyl ester, etc.);
Lower alkylthioalkyl esters (eg, methylthiomethyl ester, ethylthiomethyl ester, 1 or 2-ethylthioethyl ester, isopropylthiomethyl ester, etc.); mono (or di- or tri) halo (lower) alkyl esters (eg, 2-iodoethyl) Esters, 2,2,2-trichloroethyl esters, etc.); lower alkanoyloxy (lower) alkyl esters (eg acetoxymethyl ester, propionyloxymethyl ester, butyryloxymethyl ester, valeryloxymethyl ester, pivaloyloxymethyl) Esters, hexanoyloxymethyl esters,
Lower alkanesulfonyl (lower) alkyl esters (eg, mesylmethyl ester, 2-mesylethyl ester, etc.); having one or more suitable substituents. Al (lower) alkyl esters such as phenyl (lower) alkyl esters (such as benzyl ester, 4-methoxybenzyl ester, 4-nitrobenzyl ester, phenethyl ester, trityl ester, benzhydryl ester, bis (methoxyphenyl) methyl ester , 3,4-dimethoxybenzyl ester, 4-hydroxy-3,5-di-
aryl esters optionally having one or more suitable substituents, such as substituted or unsubstituted phenyl esters (eg, phenyl ester, tolyl ester, t-butyl phenyl ester, xylyl ester, etc.). Mesityl ester, cumenyl ester, 4-chlorophenyl ester, 4-methoxyphenyl ester, etc.); tri (lower) alkylsilyl esters; lower alkylthioesters (eg, methylthioester, ethylthioester, etc.).

Preferred examples of the compound (I) are as follows. R ¹ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, amino, protected amino [more preferably acylamino, particularly preferably lower alkanoylamino], halogen or nitro. R ²
Is hydroxy, protected hydroxy [more preferably acyloxy, particularly preferably lower alkanoyloxy], halogen, amino or protected amino [more preferably acylamino], and R ³ is carboxy,
Or acyl [more preferably lower alkoxycarbonyl; heterocyclic carbonyl optionally having 1 to 3 suitable substituents [more preferably, each halogen, nitro, lower alkyl, lower alkoxy, carboxy and protected Indolinylcarbonyl, tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl, tetrahydroquinoxalinylcarbonyl, dihydrobenzoxa, which may have 1 to 3 substituents selected from the group consisting of Dinylcarbonyl or dihydrobenzothiazinylcarbonyl; particularly preferably each having one or two substituents selected from the group consisting of halogen, nitro, lower alkyl, lower alkoxy, carboxy and esterified carboxy. May be Dolinylcarbonyl, tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl, tetrahydroquinoxalinylcarbonyl, dihydrobenzooxazinylcarbonyl or dihydrobenzothiazinylcarbonyl]; or having one or two suitable substituents Carbamoyl [more preferably, carbamoyl optionally having one or two substituents selected from the group consisting of lower alkyl and aryl optionally having one to three substituents] Particularly preferably lower alkyl, aryl (more preferably phenyl), haloaryl (more preferably halophenyl), lower alkylthioaryl (more preferably lower alkylthiophenyl), lower alkylsulfinylaryl (more preferably lower alkyl) Sulfinyl phenyl) and the acyl aryl (more preferably selected from the group consisting of lower alkylsulfonyl phenyl) 1
Or carbamoyl optionally having two substituents]], wherein R ⁴ is hydrogen or lower alkyl,
R ⁸ is hydrogen or lower alkyl, and -Z- is -O-
Or expression

Embedded image (Where n is 0, 1 or 2).

The compound (I) of the present invention and a pharmaceutically acceptable salt thereof are useful for the treatment and / or prevention of inflammatory conditions, various pains, collagen diseases, autoimmune diseases, various immune diseases and the like in humans and animals. In particular, inflammation and pain in joints and muscles (eg, rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, uric acid arthritis, etc.), inflammatory conditions of the skin (eg, sunburn, eczema, etc.), inflammatory conditions of the eye [ Eg, conjunctivitis, etc.), inflamed lung disorders [eg, asthma, bronchitis, pigeon breeder's disease, farmer's lungs, etc.], inflamed digestive conditions [eg, aphthous ulcer, Crohn's disease, atrophic gastritis, warts gastritis,
Ulcerative colitis, steatorrhea, localized ileitis, irritable bowel syndrome, etc.], gingivitis, (inflammation after surgery or injury, pain,
Swelling), inflammation-related fever, pain, other conditions, transplant rejection, systemic lupus erythematosus, scleroderma, polymyositis, polychondritis, nodular periarthritis, ankylosing spondylitis, chronic inflammatory Renal conditions [eg glomerulonephritis, membranous nephritis, etc.], rheumatic fever, Sjogren's syndrome, Behcet's disease, thyroiditis, type I diabetes, dermatomyositis, chronic active hepatitis, myasthenia gravis, idiopathic sprue, Graves' disease, Multiple sclerosis, primary biliary cirrhosis, Reiter's syndrome, autoimmune blood disorders [eg hemolytic anemia, erythrocytic anemia, idiopathic thrombocytopenia, aplastic anemia, etc.], myasthenia gravis, uvea Inflammation, contact dermatitis, psoriasis, Kawasaki disease,
Sarcoidosis, Wegener's granulomatosis, Hodgkin's disease,
It is effective for the treatment and / or prevention of cancer (eg, lung cancer, stomach cancer, colon cancer, kidney cancer, liver cancer, etc.).

Further, the compound (I) of the present invention or a pharmaceutically acceptable salt thereof can be used for a disease associated with a type I allergic reaction (eg, allergic asthma, atopic dermatitis, urticaria, allergic conjunctivitis, pollen) Disease, experimental allergic encephalomyelitis, etc.), shock (eg, septic shock, anaphylactic shock, adult respiratory distress syndrome, etc.), arteriosclerosis, thrombotic disease (thrombosis, DI
C (general intravascular blood coagulation syndrome)), ischemic disease (ischemic heart disease, ischemic brain disease, myocardial infarction, angina pectoris, etc.), cerebral vasospasm, chronic obstructive pulmonary disease, neonatal pulmonary hypertension , Erosive arthritis, polymyositis, polyarteritis nodosa, scleroderma,
Gout, bowel obstruction, DIC (general intravascular coagulation)
It is also effective for the prevention and treatment of various organ failures (eg, pulmonary failure, renal failure, liver failure, gastrointestinal bleeding, etc.) caused by advanced progression of shock or the like.
It is effective in preventing and treating diseases associated with type allergic reactions (eg, allergic asthma, atopic dermatitis, urticaria, allergic conjunctivitis, hay fever, experimental allergic encephalomyelitis, etc.). Compound (I) or a pharmaceutically acceptable salt thereof, which is an active ingredient, can be administered as it is, but is generally administered as various pharmaceutically acceptable pharmaceutical compositions. Examples of the dosage form of the pharmaceutical composition include oral solutions such as solutions, emulsions, suspensions, capsules, granules, powders, tablets, and syrups, ointments, eye drops, and nasal drops. Examples include external or topical administration, injections, suppositories and the like.

These pharmaceutical compositions include, for example, excipients such as sucrose, starch, mannitol, sorbite, lactose, glucose, cellulose, talc, calcium phosphate, calcium carbonate, cellulose, methylcellulose, hydroxypropylcellulose, polypropylpyrrolidone, gelatin,
Binders such as arabic gum, polyethylene glycol, sucrose, starch and the like, for example, disintegrants such as starch, carboxymethylcellulose, hydroxypropyl starch, sodium hydrogencarbonate, calcium phosphate, calcium carboxymethylcellulose, calcium citrate, and the like, for example, magnesium stearate, talc, lauryl Lubricants such as sodium sulfate and the like, for example, flavoring agents such as citric acid, menthol, glycine, sorbitol, orange powder and the like, preservatives such as sodium benzoate, sodium bisulfite, methylparaben, propylparaben, for example, citric acid, sodium citrate , Sodium edetate, stabilizers such as acetic acid, for example, methylcellulose, polyvinylpyrrolidone,
Suspending agents such as aluminum stearate, dispersants such as hydroxypropylmethylcellulose, solvents such as water, dissolving agents such as hydrochloric acid, emulsifiers such as sodium monostearate, flavoring agents such as lemon essence premium, For example, it is formulated by a conventional method using a preservative such as benzalkonium chloride or the like, for example, a base such as cacao butter, polyethylene glycol, microcrystalline wax, beeswax, liquid paraffin, and white petrolatum. The dosage of the pharmaceutical composition of the present invention varies depending on the age, body weight, symptoms, administration method and the like of the patient. It is administered orally or parenterally in the range of 0.01 to 300 mg / kg, preferably in the range of 3.2 to 32 mg / kg. Next, the compound of the present invention or a pharmaceutically acceptable salt thereof is converted into an IgE
Test examples demonstrate that they have an excellent inhibitory effect on antibody production.

Test Example 1: Inhibitory effect on IgE antibody production Test methods female (57BL / 6 × DBA / 2 ) F 1 and DBA /
Use 2 mice. (57BL / 6 × DBA / 2) F ₁
Mice are injected twice with DBA / 2 splenocytes at 4 day intervals to induce chronic GVH disease. 5 × 10 ^{7 for} each injection
Cells. From 3 days after the second cell injection, the drug is orally administered once a day for 8 weeks. Four weeks after the last cell injection, the amount of IgE antibody in the plasma is measured by ELISA. The activity of the compound
It is expressed as the inhibition rate (%) of gE antibody. 2. Test compound 2,3-dihydro-6- (4-fluoro-1-indolinylcarbonyl) -7-hydroxy-9-methoxy-5
-Oxo-5H-pyrido [1,2,3-de] -1,4
-Benzoxazine3. Test results

[Table 1]

Test Example 2: Toxicity test The test compound (10 mg / kg) was administered once a day to rats (5 males and 5 males) once a day for 7 days a week for 2 weeks. Hereinafter, the present invention will be described with reference to examples.

Example 1 The components in the following formulation are mixed by a conventional method and compressed to obtain a tablet.

(Equation 1)

Example 2 The components in the following formulation are mixed according to a conventional method to obtain an ointment.

(Equation 2)

Example 3 The components in the following formulation are mixed according to a conventional method to obtain a nasal drop and an eye drop.

(Equation 3)

Claims (8)

[Claims] (1) Formula (1) Wherein R ¹ is hydrogen, lower alkyl, lower alkoxy,
R ² is hydroxy, protected hydroxy, halogen, lower alkylthio, halogen, nitro, amino or protected amino;
Amino or protected amino, R ³ is hydrogen or organic group, R ⁴ is hydrogen or lower alkyl, R ⁸ is hydrogen or lower alkyl, -Z- is -O- or a compound of the formula: (Wherein n represents 0, 1 or 2), respectively. Or a pharmaceutically acceptable salt thereof as an active ingredient. 2. R ¹ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, nitro, amino or acylamino; R ² is hydroxy, acyloxy, halogen, amino or acylamino; R ³ is carboxy or acylamino The IgE antibody production inhibitor according to claim 1, which is: 3. R ¹ is hydrogen, lower alkyl, lower alkoxy, lower alkylthio, halogen, nitro, amino or alkanoylamino, R ² is hydroxy, lower alkanoyloxy, halogen, amino or acylamino, R ³ is Carboxy, lower alkoxycarbonyl, 1-3
The IgE antibody production inhibitor according to claim 2, which is a heterocyclic carbonyl optionally having one or two suitable substituents, or a carbamoyl optionally having one or two appropriate substituents. 4. R ³ is carboxy; lower alkoxycarbonyl; each having from 1 to 3 substituents selected from the group consisting of halogen, nitro, lower alkyl, lower alkoxy, carboxy and protected carboxy. May be, indolinylcarbonyl, tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl,
Tetrahydroquinoxalinylcarbonyl, dihydrobenzooxazinylcarbonyl or dihydrobenzothiazinylcarbonyl; or one selected from the group consisting of lower alkyl and aryl optionally having 1 to 3 suitable substituents 4. The IgE antibody production inhibitor according to claim 3, which is a carbamoyl which may have two substituents. 5. R ³ is carboxy; lower alkoxycarbonyl; each having one or two substituents selected from the group consisting of halogen, nitro, lower alkyl, lower alkoxy, carboxy and esterified carboxy. Optionally, indolinylcarbonyl, tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl, tetrahydroquinoxalinylcarbonyl, dihydrobenzooxazinylcarbonyl or dihydrobenzothiazinylcarbonyl; or lower alkyl, aryl, haloaryl, lower The IgE according to claim 4, which is carbamoyl optionally having one or two substituents selected from the group consisting of alkylthioaryl, lower alkylsulfinylaryl and acylaryl.
Antibody production inhibitor. 6. R ³ is carboxy; lower alkoxycarbonyl; each having one or two substituents selected from the group consisting of halogen, nitro, lower alkyl, lower alkoxy, carboxy and esterified carboxy. Optionally, indolinylcarbonyl, tetrahydroquinolylcarbonyl, tetrahydroisoquinolylcarbonyl, tetrahydroquinoxalinylcarbonyl, dihydrobenzooxazinylcarbonyl or dihydrobenzothiazinylcarbonyl; or lower alkyl, phenyl, halophenyl, lower The IgE anti-antibody according to claim 5, which is carbamoyl optionally having one or two substituents selected from the group consisting of alkylthiophenyl, lower alkylsulfinylphenyl and lower alkylsulfonylphenyl. Production inhibitor. 7. R ¹ is lower alkoxy, R ² is hydroxy, R ³ is indolinylcarbonyl optionally having halogen, R ⁴ is hydrogen, R ⁸ is hydrogen The IgE antibody production inhibitor according to claim 6, wherein -Z- is -O-. 8. The compound according to claim 1, wherein the compound is 2,3-dihydro-6- (4-
Fluoro-1-indolinylcarbonyl) -7-hydroxy-9-methoxy-5-oxo-5H-pyrido [1,
The IgE according to claim 7, which is 2,3-de] -1,4-benzoxazine or a pharmaceutically acceptable salt thereof.
Antibody production inhibitor.